Crystalline form I of imatinib mesylate

ABSTRACT

Crystalline forms of imatinib mesylate (F, G, H, I and K) and their respective characterizations are disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. patent applicationSer. No. 13/006,505, filed Jan. 14, 2011, now U.S. Pat. No. 8,189,289,which is a divisional application of U.S. patent application Ser. No.12/094,629, filed May 22, 2008, now U.S. Pat. No. 7,893,076, which is a35 U.S.C. §371 National Stage Filing of International Pat. ApplicationNo. PCT/EP2006/011240 filed Nov. 23, 2006, which claims priority under35 U.S.C. §119(e) to U.S. prov. Pat. Application Nos. a) 60/740,016,filed Nov. 28, 2005, b) 60/740,017, filed Nov. 28, 2005 and c)60/740,018, filed Nov. 28, 2005 and under 35 U.S.C. §119(a-d) to GreatBritain Pat. Appl. Nos. a) GB 0524061.9, filed Nov. 25, 2005 and b) GB0524062.7, filed Nov. 25, 2005, the entire disclosures of which arehereby incorporated by reference.

The invention relates to particular crystal forms of the methanesulfonicacid addition salt of4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide(the compound of formula I, see below), certain processes for theirpreparation, pharmaceutical compositions containing these crystal forms,and their use in diagnostic methods or, preferably, for the therapeutictreatment of warm-blooded animals, especially humans, and their use asan intermediate or for the preparation of pharmaceutical preparationsfor use in diagnostic methods or, preferably, for the therapeutictreatment of warm-blooded animals, especially humans.

BACKGROUND OF THE INVENTION

The preparation of4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide,also known as Imatinib, and its use, especially as an anti-tumour agent,are described in Example 21 of EP-A-0 564 409, which was published on 6Oct. 1993, and in equivalent applications in numerous other countries.The compound is exemplified in these publications only in free form (notas a salt).

4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamidemesylate, also known as Imatinib mesylate or STI571, the alpha and thebeta crystal form thereof, as well as its pharmaceutical use aredescribed in U.S. Pat. No. 6,894,051. Imatinib mesylate is the activeingredient of the drug Gleevec® (Glivec®) which is an approvedmedicament for the treatment of Chronic Myeloid Leukemia (CML) andgastrointestinal stromal tumors (GIST). Another polymorph of Imatinibmesylate, the so-called H1-form, is described in WO2004/106326.

It has now been surprisingly found that under certain conditions newcrystal forms of the methanesulfonate salt may be found, which aredescribed hereinafter as F-crystal form, G-crystal form, H-crystal form,I-crystal form and K-crystal form and which forms have advantageousutilities and properties.

BRIEF DESCRIPTION OF THE INVENTION

The invention is described in more detail in the following with the helpof drawings and other aids.

The invention relates especially to essentially pure crystal forms,preferably those which are referred to hereinafter as the F-crystalform, G-crystal form, H-crystal form, I-crystal form and K-crystal formof the methanesulfonic acid addition salt of Imatinib of formula I,

BRIEF DESCRIPTION OF THE DRAWINGS

The F-crystal form of the methanesulfonic acid addition salt of acompound of formula I is characterized by lines in the X-ray diffractiondiagram observed at an angle of refraction 2theta of 8.4° and 8.6°.

FIG. 1 shows the X-ray diffraction diagram of the F-crystal form of themethanesulfonic acid addition salt of a compound of formula I. In theX-ray diagram, the angle of refraction 2theta is plotted on thehorizontal axis (x-axis) and the relative line intensity(background-corrected peak intensity) on the vertical (y-axis). X-raypowder diffraction patterns are measured on a Bruker D8 GADDS DiscoverDiffractometer with Cu Kα radiation source (Kα1 radiation, wavelengthλ=1.54060 Angström). The optical density of the lines on the film isproportional to the light intensity. The film is scanned in using a linescanner. The strongest line in the X-ray diffraction diagram is observedat an angle of refraction 2theta of 20.9°. More broadly, the F-crystalform is characterized by refractions at angles of refraction 2theta of8.4°, 8.6°, 13.3°, 16.2°, 16.8°, 17.1°, 19.5°, 20.9°, 23.6° and 24.5°.In essentially pure material of the F-crystal form of themethanesulfonic acid addition salt of a compound of formula I, lines canbe observed at angles of refraction 2theta 8.4°, 8.6°, 10.4°, 13.3,°14.7°, 16.2°, 16.8°, 17.1°, 19.5°, 20.9°, 22.2°, 23.1°, 23.6°, 24.5°,25.1°, 26.0°, 26.9°, 28.5°, 29.1° and 30.3°.

The G-crystal form of the methanesulfonic acid addition salt of acompound of formula I is characterized by a line in the X-raydiffraction diagram observed at an angle of refraction 2theta of 10.5°together with the absence of any lines between an angle of refraction2theta of 4° and 8°.

FIG. 2 shows the X-ray diffraction diagram of the G-crystal form of themethanesulfonic acid addition salt of a compound of formula I. In theX-ray diagram, the angle of refraction 2theta is plotted on thehorizontal axis (x-axis) and the relative line Intensity(background-corrected peak intensity) on the vertical (y-axis). X-raypowder diffraction patterns are measured on a Bruker D8 GADDS DiscoverDiffractometer with Cu Kα radiation source (Kα1 radiation, wavelengthλ=1.54060 Angström). The optical density of the lines on the film isproportional to the light intensity. The film is scanned in using a linescanner. In the X-ray diffraction diagram of the G-crystal form linesare observed at an angle of refraction 2theta of 10.5°, 18.1° and 18.7°.More broadly, the G-crystal form is characterized by refractions atangles of refraction 2theta of 10.5°, 15.0°, 17.2°, 18.1°, 18.7°, 19.2°,21.1° and 21.3°. In essentially pure material of the G-crystal form ofthe methanesulfonic acid addition salt of a compound of formula I, linescan be observed at angles of refraction 2theta 10.5°, 12.9°, 13.9°,14.1°, 15.0°, 16.6°, 17.2°, 17.5°, 18.1°, 18.7°, 19.2°, 19.8°, 20.6°,21.1°, 21.3°, 21.7°, 22.1°, 22.8°, 23.9°, 24.3°, 25.1° and 28.6°.

The H-crystal form of the methanesulfonic acid addition salt of acompound of formula I is characterized by a line in the X-raydiffraction diagram observed at an angle of refraction 2theta of 32.9°.

FIG. 3 shows the X-ray diffraction diagram of the H-crystal form of themethanesulfonic acid addition salt of a compound of formula I. In theX-ray diagram, the angle of refraction 2theta is plotted on thehorizontal axis (x-axis) and the relative line intensity(background-corrected peak intensity) on the vertical (y-axis). X-raypowder diffraction patterns are measured on a Bruker D8 GADDS DiscoverDiffractometer with Cu Kα radiation source (Kα1 radiation, wavelengthλ=1.54060 Angström). The optical density of the lines on the film isproportional to the light intensity. The film is scanned in using a linescanner. In the X-ray diffraction diagram the H-crystal form isdominated by a line at an angle of refraction 2theta of 25.1°. Morebroadly, the H-crystal form is characterized by refractions at angles ofrefraction 2theta of 10.5°, 22.8°, 25.1° and 32.9°. In essentially purematerial of the H-crystal form of the methanesulfonic acid addition saltof a compound of formula I, lines can be observed at angles ofrefraction 2theta 10.5°, 13.8°, 15.7°, 18.1°, 21.0°, 22.8°, 24.3°,25.1°, 26.3°, 29.7° and 32.9°.

The I-crystal form of the methanesulfonic acid addition salt of acompound of formula I is characterized by a line in the X-raydiffraction diagram observed at an angle of refraction 2theta of 12.9°together with the absence of any lines at an angle of refraction 2thetabelow 9° and above 29°.

FIG. 4 shows the X-ray diffraction diagram of the I-crystal form of themethanesulfonic acid addition salt of a compound of formula I. In theX-ray diagram, the angle of refraction 2theta is plotted on thehorizontal axis (x-axis) and the relative line intensity(background-corrected peak intensity) on the vertical (y-axis). X-raypowder diffraction patterns are measured on a Bruker D8 GADDS DiscoverDiffractometer with Cu Kα radiation source (Kα1 radiation, wavelengthλ=1.54060 Angström). The optical density of the lines on the film isproportional to the light intensity. The film is scanned in using a linescanner. In the X-ray diffraction diagram of the I-crystal form linesare observed at an angle of refraction 2theta of 12.9°, 17.1°, 20.9°,23.9° and 24.3°. More broadly, the I-crystal form is characterized byrefractions at angles of refraction 2theta of 12.9°, 14.1°, 17.1°,18.0°, 18.7°, 19.1°, 19.8°, 20.9°, 23.9°, 24.3° and 25.2°. Inessentially pure material of the I-crystal form of the methanesulfonicacid addition salt of a compound of formula I, lines can be observed atangles of refraction 2theta 9.6°, 12.9°, 14.1°, 15.2°, 15.6°, 17.1°,18.0°, 18.7°, 19.1°, 19.8°, 20.9°, 23.4°, 23.9°, 24.3°, 25.2° and 28.4°.

The K-crystal form of the methanesulfonic acid addition salt of acompound of formula I is characterized by a line in the X-raydiffraction diagram observed at an angle of refraction 2theta of 37.9°.

FIG. 5 shows the X-ray diffraction diagram of the K-crystal form of themethanesulfonic acid addition salt of a compound of formula I. In theX-ray diagram, the angle of refraction 2theta is plotted on thehorizontal axis (x-axis) and the relative line intensity(background-corrected peak intensity) on the vertical (y-axis). X-raypowder diffraction patterns are measured on a Bruker D8 GADDS DiscoverDiffractometer with Cu Kα radiation source (Kα1 radiation, wavelengthλ=1.54060 Angström). The optical density of the lines on the film isproportional to the light intensity. The film is scanned in using a linescanner. In the X-ray diffraction diagram the K-crystal form is furthercharacterized by a line at an angle of refraction 2theta of 21.0°. Morebroadly, the K-crystal form is characterized by refractions at angles ofrefraction 2theta of 12.1°, 14.1°, 18.2°, 18.4°, 21.0°, 23.4° and 28.4°.In essentially pure material of the K-crystal form of themethanesulfonic acid addition salt of a compound of formula I, lines canbe observed at angles of refraction 2theta 12.1°, 12.9°, 13.6°, 14.1°,15.2°, 17.2°, 18.2°, 18.4°, 19.8°, 21.0°, 22.4°, 23.4°, 24.3°, 25.2°,28.4°, 29.2° and 37.9°.

DETAILED DESCRIPTION OF THE INVENTION

The term “essentially pure” is understood in the context of the presentinvention to mean especially that at least 90, preferably at least 95,and most preferably at least 99 percent by weight of the crystals of anacid addition salt of formula I are present in the specified crystalform according to the invention.

In the context with stating that the F-crystal form of themethanesulfonic acid addition salt of a compound of formula I exhibitsan X-ray diffraction diagram essentially as in FIG. 1, the term“essentially” means that at least the major lines of the diagramdepicted in FIG. 1, i.e. those having a relative line intensity of morethan 20%, especially more than 30%, as compared to the most intense linein the diagram, have to be present.

Alternatively, the F-crystal form of the methanesulfonic acid additionsalt of a compound of formula I is characterized by a DSC curve showinga melting event at 95° C. followed by an exothermic recrystallizationand a second melting at about 223° C.

In one preferred embodiment, the essentially pure methanesulfonic acidaddition salt of a compound of formula I in the F-crystal form shows theX-ray diffraction diagram indicated in FIG. 1.

High preference is also given for the F-crystal form of themethanesulfonic acid addition salt of a compound of formula I whichshows an X-ray diffraction diagram of the type shown in FIG. 1, in whichthe relative peak intensities of each peak do not deviate by more than10% from the relative peak intensities in the diagram shown in FIG. 1,especially an X-ray diffraction diagram identical to that shown in FIG.1.

In the context with stating that the G-crystal form of themethanesulfonic acid addition salt of a compound of formula I exhibitsan X-ray diffraction diagram essentially as in FIG. 2, the term“essentially” means that at least the major lines of the diagramdepicted in FIG. 2, i.e. those having a relative line intensity of morethan 20%, especially more than 30%, as compared to the most intense linein the diagram, have to be present.

In one preferred embodiment, the essentially pure methanesulfonic acidaddition salt of a compound of formula I in the G-crystal form shows theX-ray diffraction diagram indicated in FIG. 2.

High preference is also given for the G-crystal form of themethanesulfonic acid addition salt of a compound of formula I whichshows an X-ray diffraction diagram of the type shown in FIG. 2, in whichthe relative peak intensities of each peak do not deviate by more than10% from the relative peak intensities in the diagram shown in FIG. 2,especially an X-ray diffraction diagram identical to that shown in FIG.2.

In the context with stating that the H-crystal form of themethanesulfonic acid addition salt of a compound of formula I exhibitsan X-ray diffraction diagram essentially as in FIG. 3, the term“essentially” means that at least the major lines of the diagramdepicted in FIG. 3, i.e. those having a relative line intensity of morethan 20%, especially more than 30%, as compared to the most intense linein the diagram, have to be present.

In another preferred embodiment, the essentially pure methanesulfonicacid addition salt of a compound of formula I in the H-crystal formshows the X-ray diffraction diagram indicated in FIG. 3.

High preference is also given for the H-crystal form of themethanesulfonic acid addition salt of a compound of formula I whichshows an X-ray diffraction diagram of the type shown in FIG. 3, in whichthe relative peak intensities of each peak do not deviate by more than10% from the relative peak intensities in the diagram shown in FIG. 3,especially an X-ray diffraction diagram identical to that shown in FIG.3.

In the context with stating that the I-crystal form of themethanesulfonic acid addition salt of a compound of formula I exhibitsan X-ray diffraction diagram essentially as in FIG. 4, the term“essentially” means that at least the major lines of the diagramdepicted in FIG. 4, i.e. those having a relative line intensity of morethan 20%, especially more than 30%, as compared to the most intense linein the diagram, have to be present.

In a further preferred embodiment, the essentially pure methanesulfonicacid addition salt of a compound of formula I in the I-crystal formshows the X-ray diffraction diagram indicated in FIG. 4.

High preference is also given for the I-crystal form of themethanesulfonic acid addition salt of a compound of formula I whichshows an X-ray diffraction diagram of the type shown in FIG. 4, in whichthe relative peak intensities of each peak do not deviate by more than10% from the relative peak intensities in the diagram shown in FIG. 4,especially an X-ray diffraction diagram identical to that shown in FIG.4.

In the context with stating that the K-crystal form of themethanesulfonic acid addition salt of a compound of formula I exhibitsan X-ray diffraction diagram essentially as in FIG. 5, the term“essentially” means that at least the major lines of the diagramdepicted in FIG. 5, i.e. those having a relative line intensity of morethan 20%, especially more than 30%, as compared to the most intense linein the diagram, have to be present.

In another preferred embodiment, the essentially pure methanesulfonicacid addition salt of a compound of formula I in the K-crystal formshows the X-ray diffraction diagram indicated in FIG. 5.

High preference is also given for the K-crystal form of themethanesulfonic acid addition salt of a compound of formula I whichshows an X-ray diffraction diagram of the type shown in FIG. 5, in whichthe relative peak intensities of each peak do not deviate by more than10% from the relative peak intensities in the diagram shown in FIG. 5,especially an X-ray diffraction diagram identical to that shown in FIG.5.

The invention expressly relates also to those forms of themethanesulfonic acid addition salt of a compound of formula I in whichcrystals of the F-crystal form, G-crystal form, H-crystal form,I-crystal form and K-crystal form are present along with other crystalforms, in particular the α-crystal form, the β-crystal form, and/or theamorphous form of the Imatinib mesylate. Preferred, however, is theessentially pure form in the F-crystal form, G-crystal form, H-crystalform, I-crystal form or K-crystal form.

Particularly special preference is for the crystal forms of themethanesulfonic acid addition salt of a compound of formula I obtainableas described in the Examples.

One utility of the F-crystal form, G-crystal form, H-crystal form,I-crystal form and K-crystal form of the methanesulfonic acid additionsalt of a compound of formula I is the use as an intermediate for thepreparation of a distinct crystal form of the methanesulfonic acidaddition salt of a compound of formula I, especially the β-crystal form.The (preferably essentially pure) β-crystal form is obtainable by

-   a) digesting the F-crystal form, G-crystal form, H-crystal form,    I-crystal form or the K-crystal form of the methanesulfonic acid    addition salt of a compound of formula I with a suitable polar    solvent, especially an alcohol, most especially methanol, or also a    ketone (especially in a mixture with water, for example    water/acetone), typically acetone, a N,N-di-lower alkyl-lower    alkanecarboxamide, typically N,N-dimethylformamide or -acetamide, or    a hydrophilic ether, typically dioxane, preferably in the presence    of some water, or mixtures thereof, in suspension at a suitable    temperature, preferably a temperature between 20 and 50° C., for    example at about 25° C., or-   b) dissolving the F-crystal form, G-crystal form, H-crystal form,    I-crystal form or the K-crystal form of the methanesulfonic acid    addition salt of a compound of formula I with a suitable polar    solvent, such as especially an alcohol, typically methanol or    ethanol, a ketone (especially in a mixture with water, for example    water/acetone) typically acetone, a N,N-di-lower alkyl-lower    alkanecarboxamide, typically N,N-dimethylformamide or -acetamide, or    a hydrophilic ether, typically dioxane, or mixtures thereof,    preferably in the presence of some water, at a suitable temperature,    especially after heating the solvent, or while warming during the    dissolution process, in both cases preferably to 25° C. up to the    reflux temperature of the reaction mixture, and then initiating    crystallisation by adding a small amount of the β-crystal form as    seed crystal at a suitable temperature, for example between 0 and    70° C., preferably between 20 and 70° C.

One of the advantages of having access to different crystal forms of thecompound of formula I is the fact that distinct crystal forms are proneto incorporate distinct impurities upon crystallization, i.e. animpurity incorporated in crystal form β is not necessarily alsoincorporated in the F-crystal form, G-crystal form, H-crystal form,I-crystal form or K-crystal form. With other words, preparingconsecutively distinct crystal forms of the same material increases thepurity of the finally obtained substance. Furthermore, distinct crystalforms display different physical properties such as melting points,hygroscopicities, solubilities, flow properties or thermodynamicstabilities, and, hence, distinct crystal forms allow the choice of themost suitable form for a certain use or aspect, e.g. the use as anintermediate in the process of drug manufacture or in distinctadministration forms like tablets, capsules, ointments or solutions.

The F-crystal form, G-crystal form, H-crystal form, I-crystal form andK-crystal form of the methanesulfonic acid addition salt of a compoundof formula I possess valuable pharmacological properties and may, forexample, be used as an anti-tumour agent or as an agent to treatrestenosis.

The present invention relates especially to the F-crystal form,G-crystal form, H-crystal form, I-crystal form and K-crystal form of themethanesulfonic acid addition salt of a compound of formula I in thetreatment of one of the said diseases mentioned herein or in thepreparation of a pharmacological agent for the treatment thereof.

The antiproliferative, especially anti-tumour, activity of themethanesulfonic acid addition salt of a compound of formula I in vivois, for example, described for the treatment of abl-dependent tumours inNature Med. 2, 561-6 (1996).

The invention relates also to a method for the treatment of warm-bloodedanimals suffering from said diseases, especially leukemia, wherein aquantity of the F-crystal form, G-crystal form, H-crystal form,I-crystal form or K-crystal form of the methanesulfonic acid additionsalt of a compound of formula I which is effective against the diseaseconcerned, especially a quantity with antiproliferative efficacy, isadministered to warm-blooded animals in need of such treatment. Theinvention relates moreover to the use of the F-crystal form, G-crystalform, H-crystal form, I-crystal form and K-crystal form of themethanesulfonic acid addition salt of a compound of formula I for thepreparation of pharmaceutical compositions for use in treating the humanor animal body, especially for the treatment of tumours, such as gliomasor prostate tumours.

In preferred embodiments, the present invention relates to the use in ofthe F-crystal form, G-crystal form, H-crystal form, I-crystal form andK-crystal form of the methanesulfonic acid addition salt of a compoundof formula I in the treatment of one of the disorders listed below:

-   -   1. metastatic, inoperable GIST,    -   2. advanced chronic myeloid leukemia,    -   3. newly diagnosed chronic myeloid leukemia,    -   4. pediatric Philadelphia chromosome-positive chronic myeloid        leukemia,    -   5. Philadelphia chromosome-positive acute lymphocytic leukemia        (ALL),    -   6. glioblastoma multiforme, preferably in combination with        hydroxyurea,    -   7. dermatofibrosarcoma protuberans (DFSP),    -   8. hypereosinophilic sindrome (HES), and    -   9. chronic myelomonocytic leucemia (CMML).

Depending on species, age, individual condition, mode of administration,and the clinical picture in question, effective doses, for example dailydoses of about 50-2500 mg, preferably 100-1000 mg, especially 250-800mg, of Imatinib having the F-crystal form G-crystal form, H-crystalform, I-crystal form or the K-crystal form, are administered towarm-blooded animals of about 70 kg bodyweight. Preferably, dailydosages of 400 mg or 600 mg are administered orally once daily,preferably together with a meal and a large glass of water (about 200mL). 800 mg daily dosages are preferably administered in the form of 400mg dosages twice daily together with food.

The F-crystal form, G-crystal form, H-crystal form, I-crystal form andK-crystal form described herein can be utilized to prepare stablepharmaceutical dosage forms. Hence, the invention relates also topharmaceutical preparations which contain an amount, especially aneffective amount for prevention or treatment of one of the diseasesmentioned herein, of the methanesulfonic acid addition salt of acompound of formula I in the F-crystal form, G-crystal form, H-crystalform, I-crystal form or K-crystal form, together with pharmaceuticallyacceptable carriers which are suitable for topical, enteral, for exampleoral or rectal, or parenteral administration and may be inorganic ororganic and solid or liquid. Especially tablets or gelatin capsulescontaining the active substance together with diluents, for examplelactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/orglycerin, and/or lubricants, for example silica, talc, stearic acid, orsalts thereof, typically magnesium or calcium stearate, and/orpolyethylene glycol, are used for oral administration. Tablets maylikewise contain binders, for example magnesium aluminium silicate,starches, typically corn, wheat or rice starch, gelatin,methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and, if so desired, disintegrants, for examplestarches, agar, alginic acid, or a salt thereof, typically sodiumalginate, and/or effervescent mixtures, or adsorbents, colouring agents,flavours, and sweetening agents. The pharmacologically active compoundsof the present invention may further be used in the form of preparationsfor parenteral administration or infusion solutions. Such solutions arepreferably isotonic aqueous solutions or suspensions, these possiblybeing prepared before use, for example in the case of lyophilisedpreparations containing the active substance either alone or togetherwith a carrier, for example mannitol. The pharmaceutical substances maybe sterilised and/or may contain excipients, for example preservatives,stabilisers, wetting agents and/or emulsifiers, solubilisers, salts forthe regulation of osmotic pressure, and/or buffers. The presentpharmaceutical preparations which, if so desired, may contain furtherpharmacologically active substances, are prepared in a manner known perse, for example by means of conventional mixing, granulating, coating,dissolving or lyophilising processes, and contain from about 1% to 100%,especially from about 1% to about 20%, of the active substance orsubstances. In a preferred embodiment, the tablet or capsule contains 50mg 100 mg of the of the methanesulfonic acid addition salt of a compoundof formula I in the F-crystal form, G-crystal form, H-crystal form,I-crystal form or K-crystal form, optionally together withpharmaceutically acceptable carriers.

In one embodiment, the capsule is a hard gelatine capsule containing adry powder blend. The capsule shell preferably contains gelatine andtitanium dioxide as well as red iron oxide. The ratio of weight ofcapsule fill to capsule shell is preferably between about 100:25 and100:50, more preferably between 100:30 and 100:40.

In another embodiment, a film coated tablet is used comprising 100 mg,400 mg or 800 mg drug substance together with inactive excepientsselected from colloidal anhydrous silica, polyvinylpyrrolidone,magnesium stearate and microcrystalline cellulose.

The following Examples illustrate the invention without limiting thescope thereof. Temperatures are given in degrees Celsius (° C.).

EXAMPLES Example 1 Preparation of Crystalline Form F of ImatinibMesylate Using Benzyl Alcohol

About 500 mg of Imatinib mesylate is first dissolved in about 100 ml ofwater. About 50 μl of the stock solution is dispensed manually into aCRISSY 96-well block, to have a total amount of drug substance of 5 mgper well. The solution is flushed with nitrogen at room temperature todry the solution. The dry precipitate is resuspended with 250 μl ofbenzyl alcohol. The suspension or solution is agitated using High-speedvortexer at about 45-55° C. for about 2 hrs. The solution is thenallowed to evaporate at 45° C. to 55° C. under a stream of nitrogen.

Example 2 Preparation of Crystalline Form F of Imatinib Mesylate Using aMixture of Benzyl Alcohol and Ethyl Acetate

About 500 mg of Imatinib mesylate is first dissolved in about 100 ml ofwater. About 50 μl of the stock solution is dispensed manually into aCRISSY 96-well block, to have a total amount of drug substance of 5 mgper well. The solution is flushed with nitrogen at room temperature todry the solution. The dry precipitate is resuspended with a mixture of222 μl of benzyl alcohol and 28 μl of ethyl acetate. The suspension orsolution is agitated using High-speed vortexer at about 45-55° C. forabout 2 hrs. The solution is then allowed to evaporate at 45° C. to 55°C. under a stream of nitrogen.

Example 3 Preparation of Crystalline Form F of Imatinib Mesylate Using aMixture of Benzyl Alcohol and 1,4-Dioxane, 3-Pentanone or DiisopropylEther

About 500 mg of Imatinib mesylate is first dissolved in about 100 ml ofwater. About 50 μl of the stock solution is dispensed manually into aCRISSY 96-well block, to have a total amount of drug substance of 5 mgper well. The solution is flushed with nitrogen at room temperature todry the solution. The dry precipitate is resuspended with a mixture of214 μl of benzyl alcohol and 36 μl of 1,4-dioxane, 3-pentanone ordiisopropyl ether. The suspension or solution is agitated usingHigh-speed vortexer at about 45-55° C. for about 2 hrs. The solution isthen allowed to evaporate at 45° C. to 55° C. under a stream ofnitrogen. The crystals obtained from the mixture consisting of benzylalcohol/diisopropyl ether. A DSC curve (recorded using a Perkin ElmerDSC-7 instrument with a heating rate of 10K/min and a sample mass ofabout 0.7 mg) shows a melting event at 95° C. followed by an exothermicrecrystallization and a second melting at about 223° C.

Example 4 Preparation of Crystalline Form F of Imatinib Mesylate Using aMixture of Benzyl Alcohol and Acetonitrile or Dimethyl Formamide

About 500 mg of Imatinib mesylate is first dissolved in about 100 ml ofwater. About 50 μl of the stock solution is dispensed manually into aCRISSY 96-well block, to have a total amount of drug substance of 5 mgper well. The solution is flushed with nitrogen at room temperature todry the solution. The dry precipitate is resuspended with a mixture of200 μl of benzyl alcohol and 50 μl of acetonitrile or dimethylformamide. The suspension or solution is agitated using High-speedvortexer at about 45-55° C. for about 2 hrs. The solution is thenallowed to evaporate at 45° C. to 55° C. under a stream of nitrogen.

Example 5 Tablets with Imatinib Mesylate, F-Crystal Form

Tablets containing 100 mg of the active substance named in the title areusually prepared in the following composition:

Composition Active ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL  20 mg Aerosil  2 mg Magnesium stearate  5 mg 447 mg

Preparation: The active substance is mixed with carrier materials andcompressed on a tableting machine (Korsch EKO, punch diameter 10 mm).

-   Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).-   PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany).-   Aerosil is silicon dioxide (Degussa, Germany).

Example 6 Capsules with Imatinib Mesylate, F-Crystal Form

Capsules containing 100 mg of the compound named in the title as activesubstance are usually prepared in the following composition:

Composition Active ingredient   100 mg Avicel   200 mg PVPPXL   15 mgAerosil    2 mg Magnesium stearate  1.5 mg 318.5 mg

The capsules are prepared by mixing the components and filling themixture into hard gelatin capsules, size 1.

Example 7 Preparation of Crystalline Form G of Imatinib Mesylate Using aMixture of 3-Pentanone and Cyclohexane

About 500 mg of Imatinib mesylate is first dissolved in about 100 ml ofwater. About 50 μl of the stock solution is dispensed manually into aCRISSY 96-well block, to have a total amount of drug substance of 5 mgper well. The solution is flushed with nitrogen at room temperature todry the solution. The dry precipitate is resuspended with a mixture of125 μl of 3-pentanone and 125 μl of cyclohexane. The suspension orsolution is agitated using High-speed vortexer at about 45-55° C. forabout 2 hrs. The solution is then allowed to evaporate at 45° C. to 55°C. under a stream of nitrogen.

Example 8 Tablets with Imatinib Mesylate, G-Crystal Form

Tablets containing 100 mg of the active substance named in the title areusually prepared in the following composition:

Composition Active ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL  20 mg Aerosil  2 mg Magnesium stearate  5 mg 447 mg

Preparation: The active substance is mixed with carrier materials andcompressed on a tableting machine (Korsch EKO, punch diameter 10 mm).

-   Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).-   PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany).-   Aerosil is silicon dioxide (Degussa, Germany).

Example 9 Capsules with Imatinib Mesylate, G-Crystal Form

Capsules containing 100 mg of the compound named in the title as activesubstance are usually prepared in the following composition:

Composition Active ingredient   100 mg Avicel   200 mg PVPPXL   15 mgAerosil    2 mg Magnesium stearate  1.5 mg 318.5 mg

The capsules are prepared by mixing the components and filling themixture into hard gelatin capsules, size 1.

Example 10 Preparation of Crystalline Form H of Imatinib Mesylate Usinga Mixture of 3-Pentanone and N,N-Dimethylformamide

About 500 mg of Imatinib mesylate is first dissolved in about 100 ml ofwater. About 50 μl of the stock solution is dispensed manually into aCRISSY 96-well block, to have a total amount of drug substance of 5 mgper well. The solution is flushed with nitrogen at room temperature todry the solution. The dry precipitate is resuspended with a mixture of125 μl of 3-pentanone and 125 μl of N,N-dimethylformamide. Thesuspension or solution is agitated using High-speed vortexer at about45-55° C. for about 2 hrs. The solution is then allowed to evaporate at45° C. to 55° C. under a stream of nitrogen.

Example 11 Tablets with Imatinib Mesylate, H-Crystal Form

Tablets containing 100 mg of the active substance named in the title areusually prepared in the following composition:

Composition Active ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL  20 mg Aerosil  2 mg Magnesium stearate  5 mg 447 mg

Preparation: The active substance is mixed with carrier materials andcompressed on a tableting machine (Korsch EKO, punch diameter 10 mm).

-   Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).-   PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany).-   Aerosil is silicon dioxide (Degussa, Germany).

Example 12 Capsules with Imatinib Mesylate, H-Crystal Form

Capsules containing 100 mg of the compound named in the title as activesubstance are usually prepared in the following composition:

Composition Active ingredient   100 mg Avicel   200 mg PVPPXL   15 mgAerosil    2 mg Magnesium stearate  1.5 mg 318.5 mg

The capsules are prepared by mixing the components and filling themixture into hard gelatin capsules, size 1.

Example 13 Preparation of Crystalline Form I of Imatinib Mesylate Usinga Mixture of Ethyl Acetate and Diethyl Ether

About 500 mg of Imatinib mesylate is first dissolved in about 100 ml ofwater. About 50 μl of the stock solution is dispensed manually into aCRISSY 96-well block, to have a total amount of drug substance of 5 mgper well. The solution is flushed with nitrogen at room temperature todry the solution. The dry precipitate is resuspended with a mixture of125 μl of ethyl acetate and 125 μl of diethyl ether. The suspension orsolution is agitated using High-speed vortexer at about 45-55° C. forabout 2 hrs. The solution is then allowed to evaporate at 45° C. to 55°C. under a stream of nitrogen.

Example 14 Tablets with Imatinib Mesylate, I-Crystal Form

Tablets containing 100 mg of the active substance named in the title areusually prepared in the following composition:

Composition Active ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL  20 mg Aerosil  2 mg Magnesium stearate  5 mg 447 mg

Preparation: The active substance is mixed with carrier materials andcompressed on a tableting machine (Korsch EKO, punch diameter 10 mm).

-   Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).-   PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany).-   Aerosil is silicon dioxide (Degussa, Germany).

Example 15 Capsules with Imatinib Mesylate, I-Crystal Form

Capsules containing 100 mg of the compound named in the title as activesubstance are usually prepared in the following composition:

Composition Active ingredient   100 mg Avicel   200 mg PVPPXL   15 mgAerosil    2 mg Magnesium stearate  1.5 mg 318.5 mg

The capsules are prepared by mixing the components and filling themixture into hard gelatin capsules, size 1.

Example 16 Preparation of Crystalline Form K of Imatinib Mesylate Usinga Mixture of Ethyl Acetate and N,N-Dimethylformamide

About 500 mg of Imatinib mesylate is first dissolved in about 100 ml ofwater. About 50 μl of the stock solution is dispensed manually into aCRISSY 96-well block, to have a total amount of drug substance of 5 mgper well. The solution is flushed with nitrogen at room temperature todry the solution. The dry precipitate is resuspended with a mixture of125 μl of 3-ethyl acetate and 125 μl of N,N-dimethylformamide. Thesuspension or solution is agitated using High-speed vortexer at about45-55° C. for about 2 hrs. The solution is then allowed to evaporate at45° C. to 55° C. under a stream of nitrogen.

Example 17 Tablets with Imatinib Mesylate, K-Crystal Form

Tablets containing 100 mg of the active substance named in the title areusually prepared in the following composition:

Composition Active ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL  20 mg Aerosil  2 mg Magnesium stearate  5 mg 447 mg

Preparation: The active substance is mixed with carrier materials andcompressed on a tableting machine (Korsch EKO, punch diameter 10 mm).

-   Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).-   PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany).-   Aerosil is silicon dioxide (Degussa, Germany).

Example 18 Capsules with Imatinib Mesylate, K-Crystal Form

Capsules containing 100 mg of the compound named in the title as activesubstance are usually prepared in the following composition:

Composition Active ingredient   100 mg Avicel   200 mg PVPPXL   15 mgAerosil    2 mg Magnesium stearate   1.5 mg 318.5 mg

The capsules are prepared by mixing the components and filling themixture into hard gelatin capsules, size 1.

What is claimed is:
 1. Crystalline form I of the methanesulfonic acidaddition salt of a compound of formula I

which is characterized by an X-ray diffraction pattern comprising peaksat a diffraction angle 2θ of: 12.9°, 14.1°, 17.1°, 18.0°, 18.7°, 19.1°,19.8°, 20.9°, 23.9°, 24.3° and 25.2°.
 2. The crystalline form accordingto claim 1, which is characterized by an X-ray diffraction patterncomprising at least a peak at diffraction angle 2θ of 12.9°.
 3. Thecrystalline form according to claim 1, which is characterized by X-raypattern comprising peaks at diffraction angle 2θ of 12.9°, 17.1°, 20.9°,23.9° and 24.3°.
 4. The crystalline form according to claim 1, which ispresent in an amount of at least 90 percent by weight, based on theweight of the compound of formula I.
 5. A pharmaceutical compositioncomprising crystalline form I of the methanesulfonic acid addition saltof a compound of formula I

which is characterized by an X-ray diffraction pattern comprising peaksat a diffraction angle 2θ of 12.9°, 14.1°, 17.1°, 18.0°, 18.7°, 19.1°,19.8°, 20.9°, 23.9°, 24.3° and 25.2°, together with a pharmaceuticallyacceptable carrier.
 6. The pharmaceutical composition according to claim5 comprising between 50 mg and 800 mg of crystalline form I of themethanesulfonic acid addition salt of a compound of formula I.
 7. Thepharmaceutical composition according to claim 5 which is a capsulecontaining a dry powder blend comprising between 50 mg and 200 mg ofcrystalline form I of the methanesulfonic acid addition salt of acompound of formula I.